Dual functional roles of Tie-2/angiopoietin in TNF-alpha-mediated angiogenesis.

Chen JX, Chen Y, DeBusk L, Lin W, Lin PC
Am J Physiol Heart Circ Physiol. 2004 287 (1): H187-95

PMID: 15210451 · DOI:10.1152/ajpheart.01058.2003

Inflammation and angiogenesis are associated with pathological disorders. TNF-alpha is a major inflammatory cytokine that also regulates angiogenesis. TNF-alpha has been shown to regulate Tie-2 and angiopoietin (Ang) expression, but the functional significance is less clear. In this study, we showed that TNF-alpha induced a weak angiogenic response in a mouse cornea assay. Systemic overexpression of Ang-1 or Ang-2 dramatically increased corneal angiogenesis induced by TNF-alpha. In the absence of TNF-alpha, neither Ang-1 nor Ang-2 promoted corneal angiogenesis. Low doses (0-25 ng/ml) of TNF-alpha increased vascular branch formation of cultured endothelial cells. Overexpression of Ang-1 or Ang-2 enhanced the effects of TNF-alpha. These data suggest that Tie-2 signaling synergistically amplifies and participates in TNF-alpha-mediated angiogenesis. In addition, high doses (>/=50 ng/ml) of TNF-alpha induced apoptosis in endothelial cells, but addition of Ang-1 or Ang-2 significantly reduced cell death. Enhanced endothelial cell survival was correlated with Akt phosphorylation. Collectively, our data reveal dual functional roles of Tie-2: low doses enhance TNF-alpha-induced angiogenesis, and high doses attenuate TNF-alpha-induced cell death. The study provides evidence supporting a role for Tie-2 in inflammatory angiogenesis.

MeSH Terms (18)

Angiopoietin-1 Angiopoietin-2 Animals Apoptosis Capillaries Cells, Cultured Cell Survival Endothelium, Vascular Humans In Vitro Techniques Mice Mice, Inbred BALB C Neovascularization, Physiologic Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Receptor, TIE-2 Tumor Necrosis Factor-alpha

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